Risperidone, powder for I.M. injection, 25 mg, 37.5 mg and 50 mg (modified release) with 2 mL diluent in pre-filled syringe, Risperdal Consta® - March 2011
Page last updated: 01 July 2011
Public Summary Document
Product: Risperidone, powder for I.M. injection,
25 mg, 37.5 mg and 50 mg (modified release) with 2 mL diluent in
pre-filled syringe, Risperdal Consta®
Sponsor: Janssen-Cilag Pty Ltd
Date of PBAC Consideration: March 2011
1. Purpose of Application
The submission sought an Authority Required (STREAMLINED) listing
for maintenance treatment of refractory bipolar I disorder, in
combination with a mood stabiliser.
2. Background
This form of risperidone had not previously been considered by the
PBAC for this indication.
At the July 2004 meeting, the PBAC recommended a Section 85
authority required listing for risperidone long acting injection
(LAI) for schizophrenia on the basis of an acceptable but high
cost-effectiveness ratio. Listing was effective on 1 February 2005
and a Streamlined Authority was effective from 1 July 2007.
3. Registration Status
Risperidone LAI was TGA registered on 18 March 2010 for:
Monotherapy for maintenance treatment to prevent the recurrence of manic or mixed episodes of bipolar I disorder in patients with a manic or mixed episode, following stabilisation with oral risperidone; and
Adjunctive maintenance treatment with lithium or sodium valproate in treatment refractory patients with bipolar I disorder who have at least 4 relapses in a 12 month period.
Risperidone LAI is also TGA registered for:
Treatment of schizophrenia and related psychoses.
4. Listing Requested and PBAC’s View
Authority required (STREAMLINED)
Maintenance treatment, in combination with a mood stabiliser, of
treatment refractory bipolar I disorder.
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Bipolar I disorder is a chronic disease that is characterised by a
cycling course through one or more manic, depressed or mixed
episodes. The onset of bipolar disorder mainly occurs in the early
twenties, but can commence in childhood. The treatment of bipolar
disorder consists of acute management of a mood episode and
maintenance of treatment to prevent or delay subsequent mood
episodes.
Current pharmacological treatment options for treatment of bipolar
I disorder may include mood stabilisers (ie lithium or valproate),
an atypical antipsychotic (ie olanzapine or quetiapine),
antidepressants and anticonvulsants.
The submission proposed that risperidone LAI would be an
alternative second line maintenance therapy in treatment refractory
bipolar patients or in patients who are relapsing due to
non-adherence.
6. Comparator
The submission nominated olanzapine as the main comparator, with
quetiapine as the secondary comparator, which was considered
appropriate by the PBAC.
7. Clinical Trials
The submission presented four direct placebo-controlled RCTs of
atypical antipsychotic treatment as adjunct therapy for maintenance
in bipolar I disorder; one of risperidone LAI, one of olanzapine
and two of quetiapine. All four trials consisted of an open-label
stabilisation phase (16 weeks for the risperidone LAI trial, 6
weeks for olanzapine and between 12-36 weeks for the quetiapine
trials), and a double-blind randomised phase (52 weeks for
risperidone LAI trial, 78 weeks for olanzapine trial and 104 weeks
for the quetiapine trials). The PBAC noted that patients in the
risperidone trial were predominantly (>80%) enrolled in
India.
The submission presented two indirect comparisons using placebo +
adjunct treatment as the common comparator:
- risperidone LAI + treatment as usual vs. olanzapine + lithium/valproate (main comparison)
- risperidone LAI + treatment as usual vs. quetiapine + lithium/valproate (supportive comparison)
The table below details the published trials presented in the
submission:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Risperidone LAI | ||
| (Trial 302) Macfadden et al | A randomised, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently. | Bipolar Disord. 2009 Dec;11(8):827-39 |
| Olanzapine | ||
| Tohen et al | Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. | Br J Pyschiatry 2004; 184; p337-45 |
| Quetiapine | ||
| Vieta et al | Efficacy and safety of quetiapine in combination with lithium or valproate for maintenance of patients with bipolar I disorder (international trial 126). | J Affect Disord, 2008; 109, 251-63 |
| Suppes et al | Maintenance treatment for patients with bipolar I disorder: results from a North American study of quetiapine in combination with lithium or valproate (trial 127). | Am J Psychiatry, 2009; 166, 476-88 |
8. Results of Trials
The primary outcome in the risperidone LAI and quetiapine trials
was time to relapse of mood episode, whilst the primary outcome in
the olanzapine trial was the time to syndromic relapse. For
olanzapine, the submission used the secondary outcome, time to
symptomatic relapse, in the indirect comparison, on the basis that
the secondary outcome is more similar to the primary outcome used
in the Risperidone LAI trial.
A summary of the results of the indirect comparisons of time to
relapse of mood event for risperidone LAI compared with olanzapine
and risperidone LAI compared with quetiapine is presented in the
table below.
| Trial ID | Risperidone LAI | Comparator | ||||
| Treatment effect HR (95% CI) | RLAI n/N (%) | PBO n/N (%) | PBO n/N (%) | COM n/N (%) | Treatment effect HR (95% CI) | |
| Risperidone LAI vs. Olanzapine | ||||||
| Trial 302 | 0.41 (0.22, 0.75) | 16/72 (22%) | 32/67 (48%) | -- | -- | |
| Tohen 2004 | -- | -- | -- | 21/38 (55%) | 11/30 (37%) | 0.44 (0.21, 0.91) |
| Indirect estimate of risperidone LAI vs olanzapine (95% CI) | 0.93 (0.36, 2.42) | |||||
| Risperidone LAI vs. Quetiapine | ||||||
| Trial 302 | 0.41 (0.22, 0.75) | 16/72 (22%) | 32/67 (48%) | -- | -- | |
| Vieta 2008 | -- | -- | -- | 180/367 (49%) | 62/336 (18.5%) | 0.28 (0.21, 0.37) |
| Suppes 2009 | -- | -- | -- | 163/313 (52%) | 63/310 (20%) | 0.32 (0.24, 0.42) |
| Pooled effect a | - | -- | -- | 343/680 (50%) | 125/646 (19%) | 0.30 (0.25, 0.37) I 2 = 0% |
| Indirect estimate of risperidone LAI vs quetiapine (95% CI) | 1.37 (0.72, 2.60) | |||||
Figures in bold are statistically significant.
Abbreviations: CI= confidence interval; COM= comparator; n= number
with event; N= number in group; RLAI= risperidone LAI; PBO=
placebo; HR= Hazard Ratio.
The PBAC noted that the trials in this setting had a high
discontinuation rate after the open label stabilisation phase,
suggesting that patients in the double-blind phase of the trials
were selected as more likely to adhere to treatment and to respond.
Discontinuations during the maintenance (double blind) phase were
also high.
Patients in the double blind phase of the risperidone LAI trial
were stabilised on risperidone LAI, which does not reflect clinical
practice in Australia.
The treatments in the common reference arms were not identical
between the risperidone LAI and olanzapine and quetiapine trials,
but comparable. Treatment as usual in the risperidone LAI trial
consisted of any number or combination of antidepressants, mood
stabilisers or anxiolytics, while in the other trials adjunct mood
stabiliser treatment with lithium or valproate was mandatory.
The PBAC noted that risperidone LAI, olanzapine and quetiapine all
demonstrated a significantly longer time to relapse compared with
placebo. Importantly, olanzapine did not demonstrate a significant
improvement for the primary outcome of the Tohen 2004 trial, time
to syndromic remission (HR 0.88, 95% CI 0.43, 1.82).
The results of the indirect comparisons of risperidone LAI versus
olanzapine (main comparison) and risperidone LAI versus quetiapine
(supportive comparison) showed risperidone LAI to be non-inferior
in terms of comparative effectiveness to olanzapine (HR 0.93 [95%
CI: 0.36, 2.42]) and quetiapine (HR 1.37 [95%CI: 0.72,
2.60]).
For PBAC’s comments on these results, see Recommendation
and Reasons.
In the clinical trial risperidone LAI was associated with
significantly more hypokinesia and sedation than placebo treatment.
Risperidone LAI was associated with clinically and statistically
significant adverse events despite the small size of the trial. The
adverse events reported were consistent with those already known
from the use of risperidone LAI in the schizophrenia
population.
Both olanzapine and quetiapine were associated with significant
weight gain in the clinical trials. Quetiapine was also linked to
sedation, somnolence and hypothyroidism compared to placebo
treatment.
9. Clinical Claim
The submission described risperidone LAI as non-inferior in terms
of comparative effectiveness and non-inferior in terms of
comparative safety compared to olanzapine (main comparison) and
quetiapine (supportive comparison), which was considered reasonable
by the PBAC.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost-minimisation analysis of
risperidone LAI compared with olanzapine.
Risperidone LAI 29.2 mg every two weeks was assumed to be
equivalent to 8.6 mg of olanzapine daily, or 506.8 mg of quetiapine
twice daily.
The submission did not include additional General Practitioner or
nurse practitioner visits for injecting risperidone LAI, and only
included pharmaceuticals in the cost-minimisation analysis.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The submission calculated that the net financial cost/year for the
PBS of risperidone LAI is likely to be less than $10 million by
Year 5 of listing.
12. Recommendation and Reasons
The PBAC recommended listing risperidone (modified release) LAI on
the PBS as an Authority Required (STREAMLINED) benefit for
maintenance treatment, in combination with lithium or sodium
valproate, of treatment refractory bipolar I disorder on a
cost-minimisation basis with oral olanzapine. The equi-effective
doses are risperidone LAI 29.2 mg every 2 weeks and olanzapine 8.6
mg daily.
The PBAC recommended that a price premium for the intramuscular
injection over oral treatment should apply, as previously accepted
by PBAC in schizophrenia, given the compliance advantage in bipolar
would be expected to be similar. The PBAC recommended that a Level
B consultation fee was appropriate to account for the additional
administration costs of the injection, assumed in the
submission’s Pre-PBAC Response to be an additional 13
consultations per year. The PBAC noted that this was consistent
with its November 2010 recommendation for paliperidone LAI.
The PBAC agreed that the restriction should specify use in
combination with lithium or sodium valproate for consistency with
the TGA approved indication. The PBAC noted that the TGA approved
indication also specifies that treatment refractory patients have
at least 4 relapses in a 12 month period. However, the PBAC agreed
that it was likely that non-adherence to treatment is a
contributing factor in patients who frequently relapse and that the
requested listing for treatment of refractory disease, without
further qualification, was appropriate.
The PBAC noted that the results of the indirect comparisons of
risperidone LAI versus olanzapine (main comparison) and risperidone
LAI versus quetiapine (supportive comparison) showed risperidone
LAI to be non-inferior in terms of comparative effectiveness to
olanzapine (HR 0.93 [95% CI: 0.36, 2.42]) and quetiapine (HR 1.37
[95%CI: 0.72, 2.60]).
However, the PBAC acknowledged that uncertainty exists with the
exchangeability of the trials used in the indirect comparisons,
noting the apparent differences between the trials as identified by
the ESC, including:
- differences in trial populations; proportion of patients considered to be rapid cyclers, ethnicity, differences in the most recent bipolar episode (manic, depressive, mixed);
- differences in trial design; length of the open-label and double-blind phases, pre-treatment, concomitant treatment, dose titration protocols;
- differences in the definition of relapse;
- use of a secondary outcome for olanzapine in the indirect comparison.
However, the PBAC noted that the percentage of patients taking
lithium and/or valproate was high in all trials and that the
treatment effect observed in the placebo arms was similar, which
supports the acceptable exchangeability of the trials.
The PBAC considered that listing of risperidone LAI on the PBS
would address the current high unmet clinical need for a PBS
subsidised long-acting atypical antipsychotic for treatment of
bipolar I disorder and that the uncertainty in the data presented
in the submission was acceptable in light of this unmet clinical
need.
The PBAC recommended that risperidone powder for I.M. injection is
suitable for inclusion in the PBS medicines for prescribing by
nurse practitioners within collaborative arrangements as a shared
care model.
Recommendation:
RISPERIDONE, powder for I.M. injection, 25 mg, 37.5 mg and 50 mg
(modified release) with 2 mL diluent in pre-filled syringe
Extend the current restriction to include:
Restriction:
Authority required (STREAMLINED)
Maintenance treatment, in combination with lithium or sodium valproate, of treatment refractory bipolar I disorder.
Note
Shared Care Model
For prescribing by nurse practitioners where care of a patient is shared between a nurse practitioner and medical practitioner in a formalised arrangement with an agreed management plan. Further information can be found in the Explanatory Notes for Nurse Practitioners.
Max qty: 2
Repeats: 5
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
Janssen-Cilag welcomes the PBAC recommendation for Risperdal CONSTA
to be listed on the PBS, to provide access to an additional
treatment option for patients with bipolar I disorder.
